Cardiac hypertrophy is defined as an adaptive form of growth in response to various stress stimuli, including chronic hypertension, mechanical overload and stress on the heart from infarction or other cardiac disease states. Hypertrophy involves increased expression of cardiac growth related proteins, contractile proteins as well as the re-emergence of several embryonic gene isoforms. Recent studies have identified a novel calcium-calmodulin dependent signaling pathway, which regulates the transcription of several cardiac hypertrophy-sensitive genes. It has been demonstrated that active calcineurin (CaN), calcium-calmodulin dependent protein kinase I, (CaM KI) and IV (CaM KIV) all up-regulate the expression of these genes. Preliminary studies indicate that cytosolic CaM Kinase II negatively regulates the CaN, CaM KI and/or CaM KIV mediated hypertrophy. This data argues for the existence of four separate mechanisms through which CaM KII negatively regulates hypertrophy-sensitive transcription (i) direct phosphorylation and inactivation of CaN resulting in the inhibition of NFAT driven hypertrophy; (ii) the direct phosphorylation and inactivation of CaM KI resulting in the inhibition of MEF-2 dependent transcription; (iii) direct phosphorylation of the histone deacetylase (HDAC)/14-3-3 beta complex by CaM KII. This phosphorylation leads to dissociation of the complex allowing HDAC4/5 to enter the nucleus and bind MEF2, thereby silencing MEF2-dependent gene transcription (iv) direct phosphorylation of members of the CREB/ATF family of transcription factors (a downstream target of CaM KI or CaM KIV) by CaM KII. The findings of the proposed investigation will, for the first time, identify a transcriptional silencing mechanism in the ventricular cardiomyocyte. Defining transcriptional silencing mechanisms in hypertrophy is crucial for the development of new drugs in the treatment of malignant cardiac hypertrophy and progression to heart failure.